POS0074 IMMUNOLOGICAL DIFFERENCES BETWEEN PsA PATIENTS WHO ARE TUMOR NECROSIS FACTOR INHIBITOR-NAIVE AND WHO HAVE INADEQUATE RESPONSE TO TUMOR NECROSIS FACTOR INHIBITORS
Authors: S. Siebert, L. Coates, G. Schett, S. P. Raychaudhuri, W. Chen, S. Gao, S. D. Chakravarty, M. Shawi, F. Lavie, E. Theander, M. Neuhold, A. Kollmeier, X. L. Xu, P. Rahman, P. J. Mease, A. Deodhar
Journal: Annals of the Rheumatic Diseases (2022)

Background A better understanding of the immunological differences between psoriatic arthritis (PsA) patients (pts) who are tumor necrosis factor inhibitor (TNFi)-naïve &amp; who have inadequate response to TNFi (TNFi-IR) may guide treatment choices. In DISCOVER-1, benefit of the IL-23p19 subunit inhibitor guselkumab (GUS) every-four-weeks (Q4W) &amp; Q8W vs placebo (PBO) in improving PsA signs &amp; symptoms was seen in adults with active PsA. 1 The Ph3b COSMOS study of GUS Q8W vs PBO in TNFi-IR PsA pts corroborated these findings. 2 Objectives Assess baseline (BL) molecular differences between TNFi-naïve &amp; -IR PsA pts &amp; investigate GUS pharmacodynamic (PD) effect on cytokine expression over time in these cohorts. Methods Serum samples collected from consenting biomarker substudy pts in DISCOVER-1 1 (TNFi-naïve [n=101] &amp; -IR [n=17]), DISCOVER-2 3 (TNFi-naïve [n=150]), &amp; COSMOS 2 (TNFi-IR [n=76]) were analyzed for selected serum cytokine levels. TNFi-IR pts in this post-hoc analysis had active PsA &amp; discontinued 1-2 TNFi due to inadequate efficacy; these pts required a TNFi-specific washout period prior to starting GUS. PD effect of GUS Q8W on cytokine levels was assessed. Differential BL cytokine expression, associations between BL cytokine levels &amp; clinical response (Psoriasis [PsO] Area &amp; Severity Index 75% improvement from BL [PASI75] &amp; American College of Rheumatology 20% improvement [ACR20]), &amp; GUS effect on cytokine levels were analyzed with a General linear model &amp; Spearman linear regression. Results BL pt demographics, disease characteristics, &amp; conventional synthetic disease-modifying antirheumatic drug (csDMARD) use were comparable between TNFi-naïve (DISCOVER-1 &amp; -2, N=251) &amp; -IR (DISCOVER-1 &amp; COSMOS, N=93) pts, with differences in mean PASI score (8.9 v 12.5), swollen joint count (SJC) (11.7 v 10.3), PsA duration (5.8 v 9.8 yrs), &amp; PsO duration (16.7 v 20.4 yrs; Table 1). BL serum IL-22 &amp; TNFα levels for pooled treatment groups were higher in TNFi-IR than -naïve pts (p&lt;0.05). At W24, GUS reduced IL-22, IL-17A/F, IL-6, C-reactive protein (CRP), &amp; serum amyloid A protein to similar levels in both cohorts (p&lt;0.05; Figure 1). W24 PASI75 responders had higher BL IL-17F levels with GUS in both cohorts (p&lt;0.05) &amp; higher IL-22 levels in TNFi-IR pts only (p&lt;0.05). A trend of upregulated BL IL-22 expression in W24 ACR20 responders was seen for TNFi-IR pts with GUS (p=0.07). Table 1. BL demographics, disease characteristics, &amp; drug use in TNFi-naïve &amp; -IR cohorts with available cytokine data in DISCOVER-1&amp;2 &amp; COSMOS.* TNFi-naïve (N=251) TNFi-IR (N=93) Age [yrs] 47.2 (11.3) 48.5 (11.1) Female, n (%) 132 (52.6) 46 (49.5) Body mass index [kg/m 2 ] 29.6 (6.1) 30.3 (6.4) Median (range) CRP [mg/dL] 0.9 (0.0-12.9) 1.0 (0.0-13.2) Log2 IL-22 / TNFα [pg/mL] 2.0 (1.4) / 1.1 (0.6) 2.5 (1.5) / 1.9 (1.2) Log2 IL-17A / F [pg/mL] -0.4 (1.5) / 1.7 (1.5) -0.1 (1.7) / 2.0 (1.6) SJC [0-66] 11.7 (7.1) 10.3 (8.3) TJC [0-68] 20.3 (13.1) 20.6 (14.2) PsA duration [yrs] 5.8 (5.9) 9.8 (8.2) PsO duration [yrs] 16.7 (12.8) 20.4 (12.0) PsO Body surface area (%) 14.8 (18.6) 19.1 (21.3) Investigator’s Global Assessment score [0-4] 2.3 (0.9) 2.3 (1.0) PASI score [0-72] 8.9 (10.6) 12.5 (12.0) Enthesitis [Y], n (%) 160 (63.7) 58 (62.4) csDMARD use [Y], n (%) 164 (65.3) 62 (66.7) Corticosteroid use (Y), n (%) 45 (17.9) 19 (20.4) Methotrexate use [Y], n (%) 136 (54.2) 54 (58.1) Data are mean (SD) unless otherwise noted. *Pts with serum CRP level ≥0.3 mg/dL, SJC ≥3, &amp; TJC ≥3 (to mimic D1 inclusion criteria 1 ). TJC = tender joint count Conclusion Elevated BL IL-22 expression &amp; association between BL IL-22 levels &amp; W24 PASI75 response, &amp; a W24 trend for an association between upregulated BL IL-22 &amp; ACR20 response, in TNFi-IR pts seen in this exploratory analysis may suggest increased involvement of the IL-23 pathway in TNFi-IR pts. GUS showed comparable &amp; significant PD effects for TNFi-naïve &amp; -IR pts, consistent with observed clinical responses. References [1]Deodhar A, et al. Lancet. 2020;395:1115-25. [2]Coates LC, et al. Ann Rheum Dis. 2021;80:140-1. [3]Mease P, et al. Lancet. 2020;395:1126-36. Disclosure of Interests Stefan Siebert Speakers bureau: AbbVie, Biogen, GSK, Janssen, Novartis, UCB, Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, GSK, Janssen, Novartis, and UCB, Laura Coates Speakers bureau: AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Medac, Novartis, Pfizer and UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Georg Schett Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Gilead, Janssen, Novartis, and UCB, Siba P Raychaudhuri Speakers bureau: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, SUN Pharma, and UCB, Consultant of: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, SUN Pharma, and UCB, Grant/research support from: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, SUN Pharma, and UCB, Warner Chen Shareholder of: Johnson &amp; Johnson, Employee of: Janssen Research &amp; Development, LLC (a wholly owned subsidiary of Johnson &amp; Johnson), Sheng Gao Shareholder of: Johnson &amp; Johnson, Employee of: Janssen Research &amp; Development, LLC (a wholly owned subsidiary of Johnson &amp; Johnson), Soumya D Chakravarty Shareholder of: Johnson &amp; Johnson, Employee of: Janssen Scientific Affairs, LLC (a wholly owned subsidiary of Johnson &amp; Johnson), May Shawi Shareholder of: Johnson &amp; Johnson, Employee of: Janssen Pharmaceutical Companies of Johnson &amp; Johnson, Frederic Lavie Shareholder of: Johnson &amp; Johnson, Employee of: Janssen Pharmaceutical Companies of Johnson &amp; Johnson, Elke Theander Shareholder of: Johnson &amp; Johnson, Employee of: Janssen Scientific Affairs, LLC (a wholly owned subsidiary of Johnson &amp; Johnson), Marlies Neuhold Shareholder of: Johnson &amp; Johnson, Employee of: Janssen Scientific Affairs, LLC (a wholly owned subsidiary of Johnson &amp; Johnson), Alexa Kollmeier Shareholder of: Johnson &amp; Johnson, Employee of: Janssen Research &amp; Development, LLC (a wholly owned subsidiary of Johnson &amp; Johnson), Xie L Xu Shareholder of: Johnson &amp; Johnson, Employee of: Janssen Research &amp; Development, LLC (a wholly owned subsidiary of Johnson &amp; Johnson), Proton Rahman Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, and UCB, Grant/research support from: Janssen and Novartis, Philip J Mease Speakers bureau: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Consultant of: AbbVie, Aclaris, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Inmagene, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Atul Deodhar Speakers bureau: AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Aurinia, Bristol Myers Squibb, Celgene, Eli Lilly, GSK, Janssen, MoonLake, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, and UCB